Pharmaceutical composition

ABSTRACT

Disclosed is an antifungal agent for external use, which is characterized by containing a compound represented by the general formula (1) below, 50-95% by mass of an alcohol, and 0.1-35% by mass of water and/or an anionic surfactant.

TECHNICAL FIELD

The present invention relates to a skin agent for external use, and morespecifically, to an antifungal agent for external use.

BACKGROUND ART

For diseases such as athlete's foot and candidiasis to be caused byfungi, medicaments such as bifonazole, butenafine, and terbinafine havebeen developed and prescribed as skin medicines for external use.

Of those, there may be exemplified, as a particularly promisingmedicament, a compound represented by a general formula (1) having aneffect of shortening a therapeutic period for diseases derived fromfungi, which has been reported in recent years as a novel imidazolecompound having an antifungal activity, especially, luliconazole, whichis an optically active substance (see JP 3278738 B). Further, suchcompound is also useful for onychomycosis, and a formulation foronychomycosis has also already been known (for example, see WO03/105841). That is, the compound represented by the general formula (1)may be said as a useful active ingredient that may be widely used formycoses (having an antifungal action).

It is generally known that an antifungal agent is used for a therapy fortinea (tinea pedis, tinea corporis, or tinea cruris), candidiasis(intertrigo or erosio interdigitalis blastomycetica), chromophytosis, orseborrheic dermatitis, for example. However, a formulation used forseborrheic dermatitis is applied to a scalp site around the hair, andthus is used in a larger amount compared with that used for mycoses ofthe body and mycoses of the hands and feet. Therefore, it is restrictedto use a solvent such as methyl ethyl ketone from the viewpoints ofpossibility of causing an irritation, flammability, and the like.Accordingly, there has been a demand for a formulation that is free ofany adverse effect such as an irritation and may be easily administered.In addition, in order to ensure an effect of an antifungal action, it ispreferred that a formulation sufficiently dissolves a drug and be in aform of a single-phase solution. Because the compound represented by thegeneral formula (1) has restricted water solubility, one problem is howto prepare a formulation in a form of a single-phase solution withoutimpairing the solubility of the compound.

Meanwhile, various studies are being conducted in order to improve thestability of a bulk drug of an antifungal agent. In particular, in acompound having an asymmetric carbon in the molecule, the maintenance ofa steric structure becomes a critical issue in addition to thesolubility. This is because the steric structure may be easily changedin a dissolution state. Any of the addition of sugars (see JP2000-169372 A) and the adjustment of a pH (see JP 06-065076 A) has beenconducted as one measure for the above, for example. In addition, it isknown that an imidazole derivative is easily dissolved by polyethyleneglycol, to thereby provide satisfactory stability (see JP 05-070351 A).However, there is no definite law for maintenance property of suchsteric structure. Thus, it may be said that the case where the stericstructure may be maintained is rare in itself. Further, such combinationis incidentally found out under the present situation. In a formulationcontaining the compound represented by the general formula (1), therehas been no finding about whether or not the maintenance of the stericstructure of the compound becomes a problem, and further, it is notknown how to achieve such maintenance of the steric structure. Undersuch backgrounds, in pharmaceutical administration and regulations,there is a demand for means for ensuring the stability suited for thecompound represented by the general formula (1).

In addition, an alcohol typified by ethanol and water are widely usedmedium ingredients in formulation. It is known that those ingredientsmay cause hydrolysis or the like to affect the stability of an activeingredient. However, there has been no finding that the ingredients havea preferred contribution to the stability in a specified mixing ratio.Further, an anionic surfactant such as sodium dodecyl sulfate has beenknown to have a surfactant action and an action of promoting medicamentpermeability, but is not in any way known for its contribution to thestability.

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

The present invention has been made under such circumstances. An objectof the present invention is to provide a stable formulation havingcharacteristics including containing a compound represented by thegeneral formula (1).

Means for Solving the Problem

The inventors of the present invention have intensively studied tosearch a stable formulation having characteristics including containinga compound represented by the general formula (1). As a result, theinventors have found that, in a formulation of a compound represented bythe general formula (1), one problem is the maintenance property of asteric structure, and the stability relating to such maintenanceproperty of a steric structure is improved by dissolving the compound inan alcohol and adding a specified proportion of water. The mass ratio ofan alcohol to water as described above is 0.1 to 35 mass % of the waterwith respect to a range of 50 to 95 mass % of the alcohol. It should benoted that such formulation system preferably takes a form of asingle-phase solution.

Based on such finding, the inventors of the present invention havecompleted the present invention. That is, the present invention is asfollows.

(1) An antifungal agent for external use, including: 1) a compoundrepresented by the general formula (1); 2) 50 to 95 mass % of analcohol; and 3) 0.1 to 35 mass % of water and/or an anionic surfactant.

(2) The antifungal agent for external use according to the item (1), inwhich the compound represented by the general formula (1) isluliconazole.

(3) The antifungal agent for external use according to the item (1) or(2), in which the antifungal agent is in a form of a single-phasesolution.

(4) The antifungal agent for external use according to any one of theitems (1) to (3), including substantially no flammable solvent excludingan alcohol.

(5) The antifungal agent for external use according to any one of theitems (1) to (4), wherein a disease to which the antifungal agent isapplied is selected from the group consisting of tinea (tinea pedis,tinea corporis, or tinea cruris), candidiasis (intertrigo or erosiointerdigitalis blastomycetica), chromophytosis, and seborrheicdermatitis.

(6) The antifungal agent for external use according to the item (5),wherein the disease to which the antifungal agent is applied isseborrheic dermatitis.

EFFECTS OF THE INVENTION

The present invention may provide a formulation in which the compoundrepresented by the general formula (1) stably exists. Such formulationmay be usefully used for seborrheic dermatitis.

BEST MODE FOR CARRYING OUT THE INVENTION

An antifungal agent for external use of the present invention includes acompound represented by the general formula (1), 50 to 95 mass % of analcohol such as ethanol, and 0.1 to 35 mass % of water. It should benoted that part or all of water may be replaced by an anionicsurfactant.

When X in the compound represented by the general formula (1) representsa halogen, preferred examples of the halogen include a chlorine atom, abromine atom, an iodine atom, and a fluorine atom. Of those, a chlorineatom is particularly preferred.

Further, the amount of the compound represented by the general formula(1) is preferably 0.01 to 20 mass % and particularly preferably 0.1 to10 mass % with respect to the total amount of an antifungal agent forexternal use.

An alcohol typified by ethanol dissolves the compound, and hence isincorporated in an amount of preferably 50 to 95 mass % and further,more preferably 70 to 90 mass % with respect to the total weight of anantifungal agent for external use. This is because the compound may notbe sufficiently dissolved and may be time-dependently precipitated whenan alcohol amount is small. Therefore, the above-mentioned amount isparticularly preferred in order to exhibit a form of a single-phasesolution.

Further, alcohols which may be mixed with water at an arbitrary ratioare preferred as alcohols other than ethanol, and specific suitableexamples include polyvalent alcohols such as 2-propanol,2-ethyl-1,3-hexanediol, propylene glycol, 1,3-butanediol, glycerin, andpolypropylene glycol. When using those alcohols other than ethanol, theyare preferably used together with ethanol, and a form in which ethanolis used together so that ethanol is incorporated in a amount of 50 mass% or more of an alcohol amount is particularly preferred. It may be saidthat those alcohols other than ethanol are preferably used in such aform that a part, in particular, a part not more than a half amount ofethanol is replaced by one kind or two or more kinds selected from thealcohols. It should be noted that the term “single-phase solution” asused herein refers to liquid substances dissolved with each other inwhich no white turbidity is observed and neither liquid crystal nor finecrystal is observed under a polarized light.

In contrast, an excess alcohol amount may impair the degree of freedomin prescription. Further, the addition of water may suppress atime-dependent change of the compound in a formulation, for example, achange of the compound into a compound having a changed steric structuresuch as an S-E isomer represented by the general formula (2) and a Zisomer represented by the general formula (3), in particular, a changeof the compound into the S-E isomer. In order to obtain the effect, thepercentage of water is preferably 0.1 to 35 mass % and more preferably 1to 30 mass % with respect to the total weight of the antifungal agentfor external use. In the case of using the formulation as a gelformulation by incorporating other aqueous thickeners and the like, thepercentage of water is, for example, preferably 5 to 35 mass % and morepreferably 10 to 30 mass % with respect to the total weight of theantifungal agent for external use.

For ingredients for improving the stability of the steric structure ofthe compound represented by the general formula (1) as described above,there are given anionic surfactants such as sodium dodecyl sulfate andsodium polyoxyethylene (4) lauryl ether phosphate in addition to water,and such ingredients may also be used in place of water. However, in theinvention of the present application, it is preferred to use only waterwithout using such ingredients because such ingredients may express anirritation in portions other than the nail. Further, an emulsifyingsystem may be adopted in the skin agent for external use of the presentinvention. However, in order to take advantage of good skin permeabilitydue to the use of an alcohol such as ethanol as a solvent, it ispreferred that the skin agent for external use of the present inventionbe in a form of a single-phase solution.

In the antifungal external agent according to the invention of thepresent application, the amount ratio of water to the alcohol ispreferably 1:99 to 4:6, more preferably 5:95 to 3:7, and particularlypreferably 1:7 to 3:5 at amass ratio. Further, when an anionicsurfactant is incorporated into the antifungal agent for external useaccording to the invention of the present application, the preferredamount ratio of the anionic surfactant to the alcohol is preferably 1:99to 4:6. Further, when water and an anionic surfactant are incorporatedinto the antifungal external agent according to the invention of thepresent application, the water and the anionic surfactant areincorporated so that the ratio of the water to the anionic surfactantcomes to preferably 20:1 to 1:1.

The antifungal agent for external use of the present invention maycontain, apart from the above ingredients, an arbitrary ingredientgenerally used for a skin agent for external use. Preferred examples ofthe arbitrary ingredient include: oils and waxes such as macadamia nutoil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castoroil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil,liquid lanolin, hydrogenated coconut oil, hydrogenated oil, Japan wax,hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotawax, lanolin, reduced lanolin, hard lanolin, and jojoba wax;hydrocarbons such as liquid paraffin, squalane, pristane, ozokerite,paraffin, ceresin, vaseline, and microcrystalline wax; higher fattyacids such as oleic acid, isostearic acid, lauric acid, myristic acid,palmitic acid, stearic acid, behenic acid, and undecylenic acid; higheralcohols such as oleyl alcohol, cetyl alcohol, stearyl alcohol,isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol,and cetostearyl alcohol; synthetic ester oils such as cetylisooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyladipate, diethyl sebacate, diisopropyl sebacate, di-2-ethylhexylsebacate, cetyl lactate, diisostearyl malate, ethylene glycoldi-2-ethylhexanoate, neopentylglycol dicaprate, di-2-heptyl undecanoicacid glyceride, tri-2-ethylhexanoic acid glyceride, trimethylolpropanetri-2-ethylhexanoate, trimethylolpropane triisostearate, and pentaneerythrite tetra-2-ethylhexanoate; oil solutions of silicone oil which isnot classified into the above-mentioned silicones and the like such asmodified polysiloxanes including amino-modified polysiloxane,polyether-modified polysiloxane, alkyl-modified polysiloxane, andfluorine-modified polysiloxane; cationic surfactants such as trimethylammonium stearyl chloride, benzalkonium chloride, and laurylamine oxide;amphoteric surfactants such as imidazoline-based amphoteric surfactants(such as a 2-cocoyl-2-imidazoliniumhydroxide-1-carboxyethyloxy-2-sodiumsalt), betaine-based surfactants (such as alkyl betaine, amide betaine,and sulfo betaine), and acylmethyl taurine; nonionic surfactants such assorbitan fatty acid esters (such as sorbitan monostearate, sorbitanmonolaurate, and sorbitan sesquioleate), glycerin fatty acids (such asglycerin monostearate), propyleneglycol fatty acid esters (such aspropyleneglycol monostearate), hydrogenated castor oil derivatives,glycerol alkyl ethers, POE sorbitan fatty acid esters (such as POEsorbitan monooleate, polyoxyethylene sorbitan monostearate, andpolyoxyethylene sorbitan monolaurate), POE sorbitol fatty acid esters(such as POE-sorbitol monolaurate), POE glycerol fatty acid esters (suchas POE-glycerylmonoisostearate), POE fatty acid esters (such aspolyethyleneglycol monooleate and POE distearate), POE alkyl ethers(such as POE lauryl ether, POE oleyl ether, and POE 2-octyldodecylether), POE alkyl phenyl ethers (such as POE octylphenyl ether and POEnonylphenyl ether), pluronic types, POE/POP alkyl ethers (such asPOE/POP 2-decyltetradecyl ether), tetronic types, POE castoroil/hydrogenated castor oil derivatives (such as POE castor oil and POEhydrogenated castor oil), sucrose fatty acid esters, and alkylglycosides; polyvalent alcohols; moisture ingredients such as sodiumpyrrolidone carboxylate, lactic acid, and sodium lactate; pH adjusterssuch as phosphoric acid and citric acid; powders such as mica, talc,kaolin, synthetic mica, and barium sulfate, whose surfaces may betreated; inorganic pigments such as colcothar, yellow iron oxide, blackiron oxide, cobalt oxide, ultramarine blue, iron blue, titanium oxide,and zinc oxide, whose surfaces may be treated; pearl agents such as micatitanium, fish scale foil, and bismuth oxychloride, whose surfaces maybe treated; organic dyes such as Red No. 202, Red No. 228, Red No. 226,Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, RedNo. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203,Blue No. 1, Green No. 201, Purple No. 201, and Red No. 204, which may belaked; organic powders such as a polyethylene powder, polymethylmethacrylate, a nylon powder, and an organopolysiloxane elastomer; ap-aminobenzoate-based ultraviolet absorbent; an anthranilate-basedultraviolet absorbent; a salicylate-based ultraviolet absorbent; acinnamate-based ultraviolet absorbent; a benzophenone-based ultravioletabsorbent; a sugar-based ultraviolet absorbent; ultraviolet absorbentssuch as 2-(2′-hydroxy-5′-t-octylphenyl)benzotriazole and4-methoxy-4′-t-butyldibenzoylmethane; lower alcohols such as ethanol andisopropanol; vitamins such as vitamin A and derivatives thereof, vitaminBs such as vitamin B₆ hydrochloride, vitamin B₆ tripalmitate, vitamin B₆dioctanoate, vitamin B₂ and derivatives thereof, vitamin B₁₂, andvitamin B₁₅ and derivatives thereof, vitamin Es such as α-tocopherol,β-tocopherol, γ-tocopherol, and vitamin E acetate, vitamin Ds, vitaminH, pantothenic acid, pantethine, and pyrroloquinoline quinone; andsolvents such as benzyl alcohol, triacetin, crotamiton, carbonicdiesters such as prolene carbonate, and ethylene glycol salicylate.

When the antifungal agent for external use of the present invention isapplied to seborrheic dermatitis, the antifungal agent preferably has anappropriate viscosity for the purpose of preventing a medicament frombeing dissipated by dripping to sites other than the applied site. Tothis end, it is preferred to incorporate a cellulose-based thickenersuch as carboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and ethylcellulose, and a gelling agentsuch as a methyl vinyl ether-maleic anhydride copolymer, an acrylicresin alkanolamine solution, polyvinylpyrrolidone, and a carboxyvinylpolymer which may be modified with an alkyl group. The total amount ofsuch gelling agent is preferably 0.01 to 5 mass % and more preferably0.1 to 2.5 mass % with respect to the total amount of the antifungalagent for external use. This is because an effect of preventing drippingmay not be exerted when the amount is too small, and a form of asingle-phase solution as one preferred mode may be impaired when theamount is too large.

Further, in the antifungal agent for external use of the presentinvention, a flammable solvent such as methyl ethyl ketone andN-methyl-2-pyrrolidone excluding an alcohol typified by ethanol out ofsolvents may be incorporated. It is preferred to incorporate theflammable solvent in an amount of 1 mass % or less with respect to thetotal amount of the antifungal agent for external use, and it is morepreferred to incorporate substantially no flammable solvent. This isbecause, even if such solvent does not exist, a form of a single-phasesolution may be achieved in the construction of the antifungal agent forexternal use of the present invention, and negative factors such aspossibility of causing an irritation and flammability possessed by thesolvent may be eliminated. The term “flammable solvent” as used hereinrefers to special flammables and first class petroleum designated underthe Fire Defense Law.

The antifungal agent for external use of the present invention may beproduced by treating the above-mentioned essential ingredient, preferredingredient, arbitrary ingredient, and the like in accordance with aconventional method, and for example, is preferably produced by suchprocedure as shown in the following examples. The antifungal agent forexternal use of the present invention produced as described above isapplied to, for example, cosmetics involving quasi drugs, skinpharmaceutical compositions for external use, and skin goods forexternal use, and is particularly preferably applied to antifungal skinmedicines for external use. The antifungal agent for external use ispreferably applied to skin medicines for seborrheic dermatitis forexternal use that are applied to a wide range of sites and areadministered to sites sensitive to an irritation because the propertiesof the antifungal agent may be highly utilized. However, the antifungalagent for external use may also be effectively applied to mycoses of thebody such as tinea corporis, mycoses of the hands and feet such as tineapedis, and onychomycosis such as tinea unguium, and hence, theapplication of the antifungal agent to such mycoses also falls withinthe technical scope of the present invention.

Hereinafter, the present invention is described in more detail by way ofexamples. However, it goes without saying that the present invention isnot limited to only such examples.

Example 1

Luliconazole was dissolved by adding an appropriate amount of ethanol.To the resulting solution, POE (20) sorbitan monostearate (“NIKKOLTS-10MV”; manufactured by Nihon Surfactant Kogyo K.K.) was graduallyadded, water was further added, and homogenization was performed (Table1). The resultant was named as Skin agent A for external use. Further,Skin agent B for external use as a control was prepared in the samemanner as in Skin agent A for external use except that ethanol was addedin place of water.

TABLE 1 Prescription of Skin agent A for external use Ingredient mass %Luliconazole 1.2 POE (20) sorbitan monostearate 7.5 Water 23.3 Ethanol68 Total 100

Form of formulation: a form of a single-phase and homogeneouslydissolved solution was confirmed through a visual check.

No irritating sensation of the formulation was confirmed.

For Skin agent A for external use and Skin agent B for external use, thetime-dependent stability of luliconazole was evaluated 1 week afterpreparation under a preservation condition at 60° C. The quantitativedetermination of an S-E isomer in which the steric structure ofluliconazole was changed was performed by HPLC (LC-20AD manufactured byShimadzu Corporation, HPLC condition: column; CHIRALCEL OD-RH 4.6×150mm, column temperature; 35° C., mobile phase; a mixed solution ofmethanol/1.8% potassium hexafluorophosphate aqueous solution (83:17,v/v), flow rate; 0.56 mL/min., and detection; 295 nm). Further, thequantitative determination of a Z isomer and other analogous substanceswas performed by HPLC (Agilent 1100 manufactured by AgilentTechnologies, HPLC condition: column; Inertsil ODS-2 4.6×150 mm, columntemperature; 40° C., mobile phase; a 0.13% sodium 1-undecane-sulfonatemixed (water/acetonitrile/acetic acid (100) (54:45:1, v/v/v)) solution,flow rate; 1.0 mL/min., and detection; 295 nm). Table 2 shows theresults.

TABLE 2 Skin agent A for external use Skin agent B for external useOther Other S-E Z analogous S-E Z analogous Preservation isomer isomersubstances isomer isomer substances period (%) (%) (%) (%) (%) (%) Attime of 0.13 0.00 0.00 0.15 0.00 0.00 start 1 week 0.88 0.07 0.05 4.480.18 0.31

Example 2

In the same manner as in Example 1, luliconazole was dissolved inethanol. To the resulting solution, POE (20) sorbitan monooleate(“NIKKOL TO-10MV”; manufactured by Nihon Surfactant Kogyo K.K.) wasgradually added, water was further added, and homogenization wasperformed to prepare Skin agent C for external use. Further, Skin agentD for external use as a control was prepared in the same manner as inSkin agent C for external use except that ethanol was added in place ofwater.

TABLE 3 Prescription of Skin agent C for external use Ingredient mass %Luliconazole 1.2 POE (20) sorbitan monooleate 9.3 Water 23.3 Ethanol66.2 Total 100

Form of formulation: a form of a single-phase and homogeneouslydissolved solution was confirmed through a visual check.

No irritating sensation of the formulation was confirmed.

For Skin agent C for external use and Skin agent D for external use, thetime-dependent stability of luliconazole was evaluated 1 week afterpreparation under a preservation condition at 60° C. The quantitativedetermination of analogous substances was performed by HPLC under thesame analysis condition as that in Example 1. Table 4 shows measurementresults.

TABLE 4 Skin agent C for external use Skin agent D for external useOther Other S-E Z analogous S-E Z analogous Preservation isomer isomersubstances isomer isomer substances period (%) (%) (%) (%) (%) (%) Attime of 0.14 0.00 0.00 0.13 0.00 0.00 start 1 week 0.46 0.05 0.05 2.690.11 0.31

Example 3

In the same manner as in Example 1, luliconazole was dissolved inethanol. To the resulting solution, polyoxyethylene hydrogenated castoroil 40 (“NIKKOL HCO-40”; manufactured by Nihon Surfactant Kogyo K. K.)was gradually added, water was further added, and homogenization wasperformed to prepare Skin agent E for external use. Further, Skin agentF for external use as a control was prepared in the same manner as inSkin agent E for external use except that ethanol was added in place ofwater.

TABLE 5 Prescription of Skin agent E for external use Ingredient mass %Luliconazole 1.2 Polyoxyethylene hydrogenated 1.4 castor oil 40 Water23.7 Ethanol 73.7 Total 100

Form of formulation: a form of a single-phase and homogeneouslydissolved solution was confirmed through a visual check.

No irritating sensation of the formulation was confirmed.

For Skin agent E for external use and Skin agent F for external use, thetime-dependent stability of luliconazole was evaluated 1 week afterpreparation under a preservation condition at 60° C. The quantitativedetermination of analogous substances was performed by HPLC under thesame analysis condition as that in Example 1. Table 6 shows measurementresults.

TABLE 6 Skin agent E for external use Skin agent F for external useOther Other S-E Z analogous S-E Z analogous Preservation isomer isomersubstances isomer isomer substances period (%) (%) (%) (%) (%) (%) Attime of 0.13 0.00 0.00 0.13 0.00 0.00 start 1 week 0.28 0.04 0.04 0.570.05 0.00

Example 4

In the same manner as in Example 1, luliconazole was dissolved inethanol. To the resulting solution, polyethylene glycol 200 (“PEG-200”;manufactured by TOHO Chemical Industry Co., LTD.) was gradually added,water was further added, and homogenization was performed to prepareSkin agent G for external use. Further, Skin agent H for external use asa control was prepared in the same manner as in Skin agent G forexternal use except that ethanol was added in place of water.

TABLE 7 Prescription of Skin agent G for external use Ingredient mass %Luliconazole 1.2 Polyethylene glycol 200 18.5 Water 17.3 Ethanol 63Total 100

Form of formulation: a form of a single-phase and homogeneouslydissolved solution was confirmed through a visual check.

No irritating sensation of the formulation was confirmed.

For Skin agent G for external use and Skin agent H for external use, thetime-dependent stability of luliconazole was evaluated 1 week afterpreparation under a preservation condition at 60° C. The quantitativedetermination of analogous substances was performed by HPLC under thesame analysis condition as that in Example 1. Table 8 shows measurementresults.

TABLE 8 Skin agent G for external use Skin agent H for external useOther Other S-E Z analogous S-E Z analogous Preservation isomer isomersubstances isomer isomer substances period (%) (%) (%) (%) (%) (%) Attime of 0.13 0.00 0.00 0.14 0.00 0.00 start 1 week 0.22 0.04 0.00 0.690.04 0.00

Example 5

In the same manner as in Example 1, luliconazole was dissolved inethanol. To the resulting solution, hydroxypropylmethylcellulose 2910(“METOLOSE 60SH-4000”; manufactured by Shin-Etsu Chemical Co., Ltd.) wasgradually added and homogeneously dispersed. Then, water was added toprepare skin agents for external use. The skin agents for external usehaving water amounts of 23.6 mass % and 17.9 mass % with respect to thetotal mass were named as Skin agent I for external use and Skin agent Jfor external use, respectively. Further, Skin agent K for external useas a control was prepared in the same manner as in Skin agent J forexternal use except that ethanol was added in place of water.

TABLE 9 Prescription of Skin agent I for external use Ingredient mass %Luliconazole 1.2 Hydroxypropylmethylcellulose 1.2 2910 Water 23.6Ethanol 74 Total 100

Form of formulation: a form of a single-phase and homogeneouslydissolved solution was confirmed through a visual check.

No irritating sensation of the formulation was confirmed.

For Skin agent I for external use, Skin agent J for external use, andSkin agent K for external use, the time-dependent stability ofluliconazole was evaluated 1 week after preparation under a preservationcondition at 60° C. The quantitative determination of analogoussubstances was performed by HPLC under the same analysis condition asthat in Example 1. Table 10 shows measurement results.

TABLE 10 Skin agent I for external use Skin agent J for external useSkin agent K for external use Other Other Other S-E Z analogous S-E Zanalogous S-E Z analogous Preservation isomer isomer substances isomerisomer substances isomer isomer substances period (%) (%) (%) (%) (%)(%) (%) (%) (%) At time of 0.14 0.00 0.00 0.15 0.02 0.00 0.18 0.00 0.00start 1 week 2.83 0.12 0.07 3.78 0.16 0.03 9.08 0.44 0.22

Example 6

In the same manner as in Example 1, luliconazole was dissolved inethanol. To the resulting solution, sodium dodecyl sulfate (“NIKKOLSLS”; manufactured by Nikko Chemicals Co., Ltd.) was gradually added andhomogeneously dispersed to prepare Skin agent L for external use.Further, Skin agent M for external use as a control was prepared in thesame manner as in Skin agent L for external use except that ethanol wasadded in place of sodium dodecyl sulfate.

TABLE 11 Prescription of Skin agent L for external use Ingredient mass %Luliconazole 1.2 Sodium dodecyl sulfate 2 Ethanol 96.8 Total 100

For Skin agent L for external use and Skin agent M for external use, thetime-dependent stability of luliconazole was evaluated 1 week afterpreparation under a preservation condition at 60° C. The quantitativedetermination of analogous substances was performed by HPLC under thesame analysis condition as that in Example 1. Table 12 shows measurementresults.

TABLE 12 Skin agent L for external use Skin agent M for external useOther Other S-E Z analogous S-E Z analogous Preservation isomer isomersubstances isomer isomer substances period (%) (%) (%) (%) (%) (%) Attime of 0.13 0.00 0.00 0.17 0.02 0.00 start 1 week 0.66 0.05 0.00 1.450.09 0.00

Those results have revealed that a single-phase solution or a gelformulation may be prepared by dissolving luliconazole with an alcoholtypified by ethanol in the skin agent for external use, and adding waterand the like, and an increase in the S-E isomer and the Z isomer havingdifferent steric structures of luliconazole may be suppressed comparedwith the case where water and the like are not compounded.

Example 7

Skin agent for external use N was prepared in the same operation as thatin Example 6 in accordance with the following prescription. Afterpreservation at 60° C. for 1 week, the amount of the S-E isomer wasmeasured by the above-mentioned technique, and as a result, a peak ofthe S-E isomer was detected only at a trace level. The skin agent forexternal use N is found out to have a similar effect.

TABLE 13 Ingredient mass % Ethanol 35.4 Water 17.4 2-propanol 46Luliconazole 1.2 Total 100

Example 8

Skin agent for external use 0 was prepared in the same operation as thatin Example 7 in accordance with the following prescription. Afterpreservation at 60° C. for 1 week, the amount of the S-E isomer wasmeasured by the above-mentioned technique, and as a result, a peak ofthe S-E isomer was detected only at a trace level. The skin agent forexternal use 0 is found to have a similar effect.

TABLE 14 Ingredient mass % Ethanol 64.6 Water 23.32-ethyl-1,3-hexanediol 10.9 Luliconazole 1.2 Total 100

Example 9

Skin agent for external use P was prepared in the same operation as thatin Example 8 in accordance with the following prescription. Afterpreservation at 60° C. for 1 week, the mass of the other analogoussubstances was measured by the above-mentioned technique, and as aresult, peaks corresponding to the substances were not observed. Theskin agent for external use P is found to have a similar effect.

TABLE 15 Ingredient mass % Ethanol 69.7 Water 5.8 Polypropylene glycol2000 23.3 Luliconazole 1.2 Total 100

INDUSTRIAL APPLICABILITY

The preparation may be performed by compounding an alcohol such asethanol and water in certain ranges into the compound represented by thegeneral formula (1), to thereby improve the stability of the compound ina formulation.

1. An antifungal agent for external use, comprising: 1) a compoundrepresented by the general formula (1); 2) 50 to 95 mass % of analcohol; and 3) 0.1 to 35 mass % of water and/or an anionic surfactant.


2. The antifungal agent for external use according to claim 1, whereinthe compound represented by the general formula (1) is luliconazole. 3.The antifungal agent for external use according to claim 1, wherein theantifungal agent is in a form of a single-phase solution.
 4. Theantifungal agent for external use according to claim 1, comprisingsubstantially no flammable solvent excluding an alcohol. 5-6. (canceled)7. A method for treating mycosis comprising administering transdermallyto a subject in need thereof a composition comprising: 1) a compoundrepresented by the general formula (1); 2) 50 to 95 mass % of analcohol; and 3) 0.1 to 35 mass % of water and/or an anionic surfactant.


8. The method according to claim 7, wherein the compound represented bythe general formula (1) is luliconazole.
 9. The method according toclaim 7, wherein the composition is in a form of a single-phasesolution.
 10. The method according to claim 7, wherein the compositioncomprises substantially no flammable solvent excluding an alcohol. 11.The method according to claim 7, wherein the mycosis is selected fromthe group consisting of tinea, candidiasis, chromophytosis, andseborrheic dermatitis.
 12. The method according to claim 11, wherein themicosis is seborrheic dermatitis.
 13. A method for stabilizing acompound represented by the general formula (1) in medicine comprisingadding 1) 50 to 95 mass % of an alcohol; and 2) 0.1 to 35 mass % ofwater and/or an anionic surfactant to a pharmaceutical composition. 14.The method according to claim 13, wherein the compound represented bythe general formula (1) is luliconazole.
 15. The method according toclaim 13, wherein the stabilizing effects are depletion of production oftheir isomers.
 16. The method according to claim 15, wherein theisomer(s) are E form and/or Z form of luliconazole.